1. Technical Field
The present invention relates to formulations for counteracting skeletal muscle cell damage and degeneration due to the effects of malnutrition and various muscle degenerative diseases.
2. Description of the Problem
The devastating effect of malnutrition on worldwide child mortality rates has been well documented. Indeed, statistical studies of worldwide mortality data indicates that approximately 70% of the millions of deaths occurring annually among children less than 5 years old in developing countries is associated with malnutrition singly, or in combination with diseases such as malaria, diarrhea, measles, or acute respiratory infections. Two forms of malnutrition prevalent in developing African and Asian countries are kwashiorkor and marasmus. Both are forms of protein-energy malnutrition characterized by growth retardation in children and wasting of subcutaneous fat and muscle. Many factors add to and promote the deleterious effects of malnutrition including ingestion of toxins and viral infection.
Chronic ingestion of fungal mycotoxins by humans, particularly cyclopiazonic acid (CPA) and aflatoxin (AFL), contribute significantly to the development of malnutrition and liver cancer, respectively. CPA, an indolic fungal metabolite, coexists with AFL, a liver carcinogen, in nature. Assays of both CPA and AFL indicate that the two mycotoxins elicit their toxic effects by independent modes of action. The mechanism of the toxicity of CPA in mammals and its role as a very common toxic food contaminant is now well established. CPA is a specific inhibitor of Ca-ATPase in the skeletal muscle (sarcoplasmic reticulum) of mammals. See Goeger et al., Biochemical Pharmacology, 37, 978-981 (1988). Ca-ATPase controls the pumping of calcium within the sarcoplasmic reticulum to effect muscle contraction or relaxation. Inhibition of Ca-ATPase by CPA prevents the pumping of calcium in the muscle cell that would otherwise be used for maintaining overall health of the cell, thus resulting in a wasting and degeneration of muscle cell tissue.
Apoptosis has also been found to occur in skeletal muscle in response to CPA-induced cell damage caused by perturbation of Ca-homeostasis and Ca-ATPase. Apoptosis is an active form of cellular death and constitutes a strictly regulated device for the removal of damaged cells. Apoptosis plays a very important physiological role during organ development and is involved in disease pathogenesis. Enhanced apoptosis of cells participates in chronic pathologies such as in muscle degenerative diseases. For example, an apoptotic phenomenon exists in the skeletal muscle of experimental models of cancer cachexia, using the rat Yoshida AH-130 ascites hepatoma (liver tumor). See van Royen et al., Biochem Biophys Res Commun, 270(2): 533-537 (Apr. 13, 2000).
Another muscular-degenerative disease is hepatocellular carcinoma (HCC), which accounts for 80-90% of all liver cancers worldwide. HCC is also one of the ten most frequent cancers worldwide, accounting for 4% of the total. Major contributory factors of HCC are presumed to be fungal toxins found in foods, such as the previously noted CPA and AFL. The incidence of HCC is prevalent in men in African and Asian countries, infecting 4 out of every 10,000 people. There has been a strong indication that mycotoxins acting in concert with other factors such as malnutrition, infectious diseases and the hepatitis B virus (HBV) could be responsible for the high incidence of HCC in Africa and Asia.
HIV also causes a form of virus-induced skeletal muscle degenerative disease, namely, AIDS. Malnutrition is common among individuals suffering from advanced HIV-disease. HIV/AIDS malnutrition has a major influence on the progression of the disease. Therefore, early and ongoing nutritional and pharmacological interventions that modify and/or control the dietary intake of a subject having HIV/AIDS can minimize the progression of the disease. In fact, nutritional supplementation of HIV/AIDS patients is necessary because it might lead to improved immune function. Additionally, dietary supplements with antioxidants (e.g., vitamins C and E) at supranutritional doses have been found to protect against oxidative damage to skeletal muscle mitochondria caused by the antiretroviral agent AZT.
Many different classes of chemicals affect Ca-homeostasis adversely. Several of these compounds also adversely affect the redox state of cells causing oxidative stress. It would therefore be advantageous to develop a pharmaceutical agent or formulation that counteracts the negative effects of skeletal muscle degenerative diseases without adversely affecting calcium levels or the redox state of the muscle cells.